Enantiomeric α-amino acids, in particular, nonproteinogenic amino acids are of exceptional and rapidly increasing popularity as important tools in protein engineering and peptide-based drug discovery. Intense research has been focused on the preparation of enantiomerically enriched unnatural α-amino acids. Several approaches, for example, bioresolution routes as well as the rhodium-catalyzed asymmetric hydrogenation of enamides have shown good promise. However, there is still a need for an efficient and technically feasible method for the convenient synthesis of different types of unnatural amino acids derivatives.
An attractive strategy to accomplish such syntheses is the enantioselective nucleophilic addition to α-imino esters. This can be useful because a new chiral center and a new carbon-carbon bond can be established in a single operation and an appropriately designed side chain can be introduced as well. Prior work in the field mainly focused on the catalytic asymmetric alkylation of α-imino ester. Nucleophiles that have been used include enol silane, allyl-metal compounds, TMS-nitronate, ketones and nitroalkanes.
Recently, the alkynylation of α-imino esters by directly adding terminal alkynes to an α-imino ester in the presence of Ag(I) salts under mild reaction conditions has been reported. See, Ji et al., “Efficient Synthesis of β,γ-alkynyl α-amino acid derivatives by Ag(I) catalyzed alkynylation of α-imino esters”, 346 ADV. SYNTH. CATAL. 42-44 (2004). However, this reported Ag(I)-catalyzed reaction, is not enantioselective even when a chiral ligand is employed, for example, aminophsophanes, diphosphanes and pybox.
Thus, there is need for a process to provide for the asymmetric terminal alkynylation of α-amino esters that can be used to synthesize optically active unnatural α-amino acids. The present invention addresses this need.